A Phase II Trial of Gefitinib in Combination with Bevacizumab as First-Line Therapy for Advanced Non-Small Cell Lung Cancer with Activating EGFR Gene Mutations: The Okayama Lung Cancer Study Group Trial 1001
A Phase II Trial of Gefitinib in Combination with Bevacizumab as First-Line Therapy for Advanced Non-Small Cell Lung Cancer with Activating EGFR Gene Mutations: The Okayama Lung Cancer Study Group Trial 1001
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DOI：
10.1097/jto.0000000000000434
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发表时间：
2015-03-01
影响因子：
20.4
通讯作者：
Kiura, Katsuyuki
中科院分区：
文献类型：
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作者：
Ichihara, Eiki;Hotta, Katsuyuki;Kiura, Katsuyuki
目的：贝伐单抗是否能增强表皮生长因子受体(EGFR)抑制剂吉非替尼对EGFR突变型非小细胞肺癌(NSCLC)的作用尚不清楚。我们进行了一项II期试验，以观察吉非替尼联合贝伐单抗作为一线治疗携带EGFR基因突变的晚期非小细胞肺癌患者的疗效和安全性。方法：42例患者接受吉非替尼250 mg/d和贝伐单抗15 mg/kg治疗，每3周一次。这项研究的主要终点是1年无进展生存率(PFS)。我们假设一年的PFS率为55%将表明潜在的有用，而一年的PFS率为40%将构成兴趣的下限。结果：42名患者进入研究，中位年龄73岁(范围42-86岁)。激活EGFR基因突变包括外显子19缺失(57%)和外显子21 L858R点突变(38%)。客观缓解率为73.8%，包括两个完全缓解率。1年PFS率为56.7%(95%可信区间为39.9~70.5)，中位PFS时间为14.4个月(95%CI为10.1~19.2)。EGFR19外显子缺失和L858R点突变患者的中位生存期分别为18.0个月和9.4个月，P=0.006。总体存活率的中位数尚未达到。严重不良反应包括3级皮疹(15%)、高血压(17%)、天冬氨酸转氨酶/丙氨酸氨基转移酶升高(17%)、蛋白尿(7%)、颅内出血(2%)和4级消化道穿孔(2%)。结论：吉非替尼联合贝伐单抗作为一线治疗方案，对于EGFR基因突变激活的晚期非小细胞肺癌患者，尤其是EGFR外显子19缺失突变患者，虽然CI下限低于40%，但仍未达到初始终点，且耐受性良好。
Purpose: Whether bevacizumab enhances the effect of the epidermal growth factor receptor (EGFR) inhibitor gefitinib on EGFR mutant non-small cell lung cancers (NSCLCs) remains unknown. We conducted a phase II trial to investigate the efficacy and safety of gefitinib when combined with bevacizumab as first-line therapy in patients with advanced NSCLC harboring EGFR gene mutations.Methods: In this trial, 42 patients with a performance status of 0 to 2 received gefitinib (250 mg/d) and bevacizumab (15 mg/kg, every 3 weeks). The primary end point of this study was the 1-year progression-free survival (PFS) rate. We assumed that a 1-year PFS rate of 55% would indicate potential usefulness and that a 1-year PFS rate of 40% would constitute the lower limit of interest.Results: Forty-two patients were enrolled in the study with a median age of 73 (range 42-86) years. Activating EGFR gene mutations included exon 19 deletion (57%) and L858R point mutations in exon 21 (38%). The objective response rate was 73.8% and included two complete responses. The 1-year PFS rate and median PFS time were 56.7% (95% confidence interval [CI] 39.9-70.5) and 14.4 months (95% CI 10.1-19.2), respectively. The median PFS differed significantly between EGFR exon 19 deletion and the L858R point mutation (18.0 versus 9.4 months, respectively; p = 0.006). The median overall survival had not yet been reached. Severe adverse events included grade 3 skin rash (15%), hypertension (17%), aspartate transaminase/alanine aminotransferase elevation (17%), proteinuria (7%), intracranial hemorrhage (2%), and grade 4 perforation of the digestive tract (2%). There were no treatment-related deaths.Conclusion: Gefitinib in combination with bevacizumab as first-line therapy seems to be a favorable and well-tolerated treatment for patients with advanced NSCLC with activating EGFR gene mutations, especially those with EGFR exon 19 deletion mutations, although the primary end point was not met because the lower limit of the CI was less than 40%.